Lurasidone, [(3aR,4S,7S,7aS)-2-(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione], is a new-generation atypical antipsychotic drug used in the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Lurasidone acts as a serotonin/dopamine receptor (5-HT2A/D2) antagonist.
U.S. Pat. No. 5,532,372 discloses the synthesis of racemic Lurasidone from trans-cyclohexane-1,2-diyldimethanol (rac-1) (Scheme 1).

Lurasidone can be obtained as a single enantiomer after chiral resolution by crystallisation with L-tartaric acid.
According to said patent, each single intermediate is isolated; the process involves the use of expensive solvents, such as acetonitrile, or solvents which are not industrially suitable, such as diethyl ether. Said process also involves the use of expensive catalysts such as crown ethers, and chromatographic purification which is difficult to apply on an industrial scale. The mesylation step used to give the intermediate rac-2 presents a low yield, and the intermediate rac-2 is used in the subsequent reaction in excess, involving a cost increase. The patent reports a quantitative yield in the rac-4 intermediate formation step, but the yields reported in the subsequent literature (see below) and experimental tests demonstrate that lower yields (80-88%) are obtained under the same reaction conditions, due to the decomposition of rac-2 promoted by strong bases such as potassium carbonate used in excess, to give decomposition products undetectable by UV detectors.
Another evident drawback of this process is that enantiopure Lurasidone has to be isolated at the end of the process from a racemic mixture with a resolution by crystallisation, followed by a further salification and crystallisation, considerably increasing the costs and environmental impact of the process.
The patent does not disclose the synthesis of imide intermediate 5 used in the last synthesis step, in reaction with the intermediate rac-4, to obtain Lurasidone racemate.
The synthesis of Lurasidone from enantiopure compounds is disclosed in WO 2012131606 and IPCOM000204532D, using the procedures and reagents reported in U.S. Pat. No. 5,532,372, and thus suffering from the same limitations and lower yields in the formation of intermediate 4 (88%).
Other patents disclose, in particular, the step involving formation of intermediate 4, which is a critical step in the synthesis of Lurasidone.
US2011003994 reports the preparation of intermediate 4 in acetonitrile in the presence of potassium carbonate, with the same procedure as used in U.S. Pat. No. 5,532,372. A similar procedure, wherein acetonitrile is used as the solvent and potassium carbonate as the base, is described in IPCOM000205160D. In both these cases the most expensive intermediate, mesylate 2, is used in a slight excess (1.02 to 1.05 molar equivalents of intermediate 2 are reacted with 1.00 molar equivalents of intermediate 3), and the yields are low (80%).
US20110263847, filed by the owner of U.S. Pat. No. 5,532,372, describes the preparation of intermediate 4 and its subsequent reaction with imide intermediate 5 to give Lurasidone. This document indicates the low yield and presence of impurities in the methods previously reported. According to the invention claimed in US20110263847, mesylate 2 is reacted in toluene with a large excess (1.5 to 15 equivalents) of amine 3. The use of this excess is justified by higher yields and purities than the preceding methods, although no procedure involves isolating products, only a study of the reaction mixtures using HPLC analysis. However, the use of a large excess of 3, both as nucleophile and as base to neutralise the methanesulfonic acid formed, involves a considerable economic cost, and the excess remains in the reaction mixture as ammonium salt, which is liable to contaminate the end product.
Similarly, US20110263848, also filed by the owner of U.S. Pat. No. 5,532,372, discloses the preparation of intermediate 4 and its subsequent reaction with imide intermediate 5 to give Lurasidone. That document indicates the low yield and the presence of impurities in the methods previously reported. According to the invention claimed in US20110263848, mesylate 2 is reacted with amine 3 in toluene, in the presence of a dibasic or tribasic phosphate and a small amount of water. Once again, the procedure for isolating the products is not described, and the yields and purities are calculated by HPLC analysis of the reaction mixtures. Although in this case too the HPLC purities of the reaction mixtures are higher than those of the procedures previously reported, said method still uses an excess of mesylate 2 to complete the reaction. The use of said excess is not only a drawback from the economic standpoint but also involves potential contamination of the product with mesylate 2 and other impurities undetectable by the normal UV detectors of HPLC instruments. Continuing the synthesis of Lurasidone in the same reaction solvent, without isolating intermediate 4, therefore involves potential pollution by substances undetectable by UV detectors.
The preparation of imide intermediate 5 is not reported in any process patent for the synthesis of Lurasidone. It can be prepared by hydrogenation of intermediate 7, deriving from anhydride 6, or from maleimide 8 by reaction with cyclopentadiene 9 (Scheme 2).

WO2011062284 reports the preparation of intermediate 7 from anhydride 6 in 30% aqueous ammonia. This procedure requires very long reaction times (about 5 days), the evaporation of large amounts of water and a crystallization, and provides rather low yields, all to the detriment of the economy and productivity of the process.
J. Am. Chem. Soc., 1944, 66, 404-407 discloses the synthesis of intermediate 7 by reacting 6 with an excess of ammonium carbonate at high temperatures (200° C.) to obtain the imide after crystallisation, with a yield below 50%. The reaction involves the production of a large amount of gas which, together with the high temperatures required, makes this procedure unsuitable for industrial production both from the economic standpoint and in terms of safety. The same article describes the preparation of intermediate 7 by direct reaction between the molten anhydride 6 and gaseous ammonia, followed by crystallisation to obtain the desired product with low yields (<50%). Said reaction also has technical and safety difficulties when scaled up for industrial production.
Beilstein J. Org. Chem. 2009, 5, No. 81 discloses the preparation of the endo diastereoisomer of intermediate 7 (endo-7) in the presence of an excess of ammonium acetate in acetic acid as solvent (Scheme 3). The reaction is carried out at 140° C. for four days, and the product is isolated by extraction after complete evaporation of the solvent. This procedure not only involves very long times, but also problems relating to evaporation of the solvent and its subsequent management as waste, which make it unattractive from the industrial standpoint.

The preparation of compounds similar to intermediate 7 is described in Heterocycles, 2006, 88, 2259-2267. The authors state that cyclic imides can be prepared from the corresponding anhydrides by reaction with ammonium chloride in the presence of considerable amounts of N,N-dimethylaminopyridine (DMAP), which acts as catalyst (about 20-50% molar compared with the substrate to be converted), or with ammonium acetate, under the effect of microwaves, also demonstrating that the reaction does not take place when a conventional heating system is used. The authors only describe the experimental procedure that uses ammonium chloride in the presence of DMAP; the reaction with ammonium acetate is not described. The reaction with NH4Cl/DMAP gives medium-high yields (about 80-90%), but microwave technology, purifications by column chromatography and the use of large amounts of DMAP as catalyst, involving considerable disadvantages in terms of cost and purification of the product, make the procedure unattractive at industrial level, due to its cost and environmental impact.
Intermediate 7 can be obtained by Diels-Alder reaction between maleimide 8 and cyclopentadiene 9, which mainly gives the endo-7 isomer, and numerous successive isomerisations with gradual enrichment of the exo isomer by crystallisations at the expense of the final yield and production times. The synthesis route is reported in IPCOM000204532D, but without experimental data. The isomerisation of similar compounds is reported in EP0297078, and involves the use of high temperatures.